N-(2-amino-4,6-dichloropyrimidine-5-yl) formamide and a process for its preparation

ABSTRACT

A novel pyrimidine derivative, N-(2-amino-4,6-dichloropyrimidine-5-yl)formamide for use, e.g., in the production of antiviral nucleotide derivatives, can be made by a process involving cyclyzing an aminomalonic ester with guanidine or its salt in the presence of a base to produce 2,5-diamino-4,6-dihydroxypyrimidine or its salt, chlorinating this product with a chlorinating agent in the presence of an amide to produce 4,6-dichloropyrimidine, and reacting the 4,6-dichloropyrimidine with an aqueous solution of a carboxylic acid to produce the N-(2-amino-4,6-dichloropyrimidine-5-yl)formamide. Novel also are 4,6-dichloropyrimidine, 4,6-dichloro-N&#39;-(dimethylaminomethylene)pyrimidine-2,5-diamine, 4,6-dichloro-N&#39;-(piperidine-1-ylmethylene)pyrimidine-2,5-diamine, and a process for making 2,5-diamino-4,6-dichloropyrimidine of the formula ##STR1##

This application is a division of application Ser. No. 08/428,916, filedon Apr. 25, 1995, now U.S. Pat. No. 5,583,226.

BACKGROUND OF THE INVENTION

The invention relates to pyrimidine derivatives, for use, e.g., asintermediates in the preparation of antiviral nucleotide derivatives.

Preparation of antiviral nucleotide derivatives is described, e.g., inInternational Publication WO-91/01310. Known as intermediates in thepreparation of antiviral nucleotide derivatives are N-5-protected2,5-diamino-4,6-dichloropyrimidines as disclosed in European PatentDocument EP-A-0552758, for example. However, these compounds suffer fromthe disadvantage that they are difficult to convert into thecorresponding nucleotide derivatives.

SUMMARY OF THE INVENTION

It is an object of the invention to provide a pyrimidine derivativewhich can be used to obtain the corresponding nucleotide derivativeswith good yield, and to provide a commercially advantageous process forpreparing the pyrimidine derivative.

Preferred in these respects is a novel pyrimidine derivative designatedas N-(2-amino-4,6-dichloropyrimidine-5-yl)formamide of the formula##STR2##

A preferred process for makingN-(2-amino-4,6-dichloropyrimidine-5-yl)formamide comprises the steps of(a) cyclyzing an aminomalonic ester with guanidine or its salt in thepresence of a base to produce 2,5-diamino-4,6-dihydroxypyrimidine or itssalt, (b) chlorinating this product with a chlorinating agent in thepresence of an amide to produce 4,6-dichloropyrimidine, and (c) reactingthe 4,6-dichloropyrimidine with an aqueous solution of a carboxylic acidto produce the N-(2-amino-4,6-dichloropyrimidine-5-yl)formamide.

DETAILED DESCRIPTION

In step (a), an aminomalonic ester of the general formula ##STR3## whereR₁ denotes a C₁ -C₆ -alkyl group or its salt, is cyclized with guanidineor its salt in the presence of a base to give2,5-diamino-4,6-dihydroxypyrimidine of the formula ##STR4## or its salt.The aminomalonic esters of the general formula II which are employed asstarting compounds may be obtained in well-known manner by amidating thecorresponding malonic ester derivatives.

An alkali metal alcoholate, such as, e.g., sodium or potassiummethoxide, or sodium or potassium ethoxide, is conveniently used as thebase, in conformity with EP-A-0552758. In-situ-formed sodium methoxidein methanol or sodium ethoxide in ethanol is preferably employed.

Conveniently used as the salts of the aminomalonic ester and ofguanidine are their hydrochloride or hydrobromide salts.

The cyclization is conveniently carried out at a temperature of betweenroom temperature and the reflux temperature of the relevant solvent,preferably at the reflux temperature.

After a customary reaction time of between 2 and 6 h, the intermediateof the formula III can then be isolated where appropriate, usingcustomary methods of preparation. The synthesis of the end product ofthe formula I is preferably carried out without isolating theintermediate of the formula III.

Step (b) is carried out by chlorinating the intermediate of the formulaIII, or its salt, with a chlorinating agent in the presence of an amideof the general formula ##STR5## to form a 4,6-dichloropyrimidine of thegeneral formula ##STR6##

The substituent R₅ denotes --NH₂. The substituent R₂ denotes either

(i) a 5- or 6-membered heterocycloalkyl radical which is optionallysubstituted on the heteroatom, such as, e.g., piperidinyl, morpholinyl,thiomorpholinyl, pyrrolidinyl or N-methylpiperazinyl, preferablypiperidinyl or pyrrolidinyl, or

(ii) NR₃ R₄, where R₃ and R₄ are identical or different and are each aC₁ -C₆ -alkyl group, such as, e.g., methyl, ethyl, propyl, isopropyl,butyl, pentyl or hexyl, preferably methyl, or a benzyl group.

Thus, N,N-dimethylformamide, N,N-diethylformamide,N,N-diisopropylformamide, N-formylpiperidine, N-formylmorpholine,N-formylthiomorpholine, N,N-methylformylpiperazine orN,N-dibenzylformamide, preferably N,N-dimethylformamide,N-formylpiperidine or N,N-dibenzylformamide may be employed as amides ofthe formula IV.

The salts of the intermediate of the formula III which are convenientlyused are its hydrochloride or hydrobromide salts, or its alkali metalsalts, such as, e.g., its sodium or potassium salt.

The chlorinating agents which may be employed are those which arefamiliar to those skilled in the art, such as, e.g., phosphorusoxychloride, thionyl chloride, sulphuryl chloride, phosphorustrichloride, phosphorus pentachloride, phosgene or diphosgene.Phosphorus oxychloride is preferably used as the chlorinating agent.

The chlorinating agent and the amide (IV) are conveniently employed in amolar ratio of from 1-to-0.55 up to 1-to-10, preferably in a molar ratioof from 1-to-0.55 up to 1-to-1.

Chlorination is conveniently carried out at a temperature of from 50° C.up to the reflux temperature of the relevant solvent.

The above-described amide can be employed as the solvent forchlorination. Additionally, chlorination can be carried out with aninert solvent. Examples of suitable inert solvents are toluene, xylene,chloroform, dichloromethane, dichloroethane or chlorobenzene, preferablytoluene or dichloroethane.

Following a customary reaction time of from 3 to 24 h, the corresponding4,6-dichloropyrimidine of the general formula V (with R₅ ═--NH₂) can beisolated in a manner familiar to those skilled in the art. These4,6-dichloropyrimidine intermediates in the preparation ofN-(2-amino-4,6-dichloropyrimidine-5-yl)formamide are novel in themselvesand are a part of the invention.4,6-dichloro-N'-(dimethylaminomethylene)pyrimidine-2,5-diamine and4,6-dichloro-N'-(piperidine-1-ylmethylene)pyrimidine-2,5-diamine 5 arepreferred representatives of the 4,6-dichloropyrimidines (V, with R₅═--NH₂).

Precursors of these 4,6-dichloropyrimidines (V) may also be isolated independence on the selected reaction conditions or working-up conditions.These precursors are likewise defined by the general formula V. R₅ thendenotes --NH--CH═O or --N═CH--R₂, where R₂ is as specified above. Theseprecursors, as novel intermediates in the preparation ofN-(2-amino-4,6-dichloropyrimidine-5-yl)formamide, are novel inthemselves and are a part of the invention.4,6-dichloro-N,N'-bis(dimethylaminomethylene)pyrimidine-2,5-diamine,4,6-dichloro-N,N'-bis(piperidine-1-ylmethylene)pyrimidine-2,5-diamine orN- 4,6-dichloro-5-(dimethylaminomethyleneamino)pyrimidine-2-yl!formamide are preferred representatives.

In step (c), the 4,6-dichloropyrimidines of the general formula V arereacted with an aqueous solution of a carboxylic acid of the generalformula

    R.sub.6 --COOH                                             VI

where R₆ denotes a C₁ -C₆ -alkyl group, branched or unbranched, or a C₃-C₆ -cycloalkyl group, to give the end product of the formula I.

Acetic acid, propionic acid, butyric acid, pentanoic acid, hexanoicacid, isobutyric acid, pivalic acid, cyclopropanecarboxylic acid,cyclopentanecarboxylic acid, or cyclohexanecarboxylic acid may beemployed as the carboxylic acid. Use of acetic acid, propionic acid orpivalic acid is particularly convenient.

Carboxylic acid is conveniently employed at a concentration of from 20to 70 vol.%, preferably of from 25 to 50 vol.%.

It was found that, if the carboxylic acid in step (c) is employed in anaqueous alcoholic solution, 2,5-diamino-4,6-dichloropyrimidine of theformula VII is formed directly. This compound can also be converted intothe corresponding nucleotide derivative. Accordingly, the process forpreparing 2,5-diamino-4,6-dichloropyrimidine of the formula ##STR7## isalso a part of the invention.

An aqueous solution of methanol, ethanol, propanol, butanol, pentanol orhexanol may be employed as the aqueous alcoholic solution.

The reaction in step (c) is conveniently carried out at a temperature offrom 50° to 100° C., preferably at a temperature of from 70° to 90° C.

Following a customary reaction time of from 1 to 10 h, the end productof the formula I or VII can be isolated using working-up methods whichare familiar to those skilled in the art. As contrasted with thepreviously known N-5-protected 2,5-diamino-4,6-dichloropyrimidines(EP-A-0552758), the novel end product of the formula I, and also thepreviously known end product of the formula VII, can be convertedreadily and with good yield into the corresponding nucleotidederivative.

EXAMPLE 1 Preparation ofN-(2-amino-4,6-dichloropyrimidine-5-yl)formamide

1.1 Preparation of4,6-dichloro-N'-(dimethylaminomethylene)pyrimidine-2,5-diamine

One-pot process:

A suspension of 25 g (117 mmol) of aminomalonic ester hydrochloride in50 ml of methanol was cooled down to 10° C., and 21.07 g of sodiummethoxide (30% in methanol) was added. This suspension was addeddrop-wise to a mixture of 63.2 g (351 mmol) of sodium methoxide (30%solution in methanol) and 12.55 g (128.7 mmol) of guanidinehydrochloride in 50 ml of methanol. The reaction mixture was heated toreflux and then stirred at this temperature for 16 hours. Subsequently,13.5 g (370 mmol) of HCl gas was passed into the warm suspension. Themethanol was then distilled off. During the distillation, a total of 200ml of toluene was slowly added drop-wise. After all the methanol hadbeen distilled out, 71.6 g (468 mmol) of POCl₃ was added drop-wise,followed by 34.2 g (468 mmol) of dimethylformamide, which was addeddrop-wise at 80° C. The mixture was left to stir at 80° C. for 17.5hours and then cooled down to room temperature; 64.7 g of K₂ CO₃,dissolved in 150 ml of water, was then added slowly. The mixture washeated once again at 50° C. for 5 hours. The mixture was then adjustedto a pH of 7 using a 30% solution of NaOH, cooled, and the product wasfiltered off. After washing with water and drying in vacuo, 23.2 g (85%)of pure product was obtained as a pale brown solid. ¹ H--NMR (DMSO, 400MHz)δ: 2.9-3.0 (2s, 6H); 6.9 (s, 2H); 7.6 (s, 1H). ¹³ C--NMR (DMSO, 100MHz): 33.5; 39.3; 130.3; 153.5; 157.0; 157.1. m.p.: 195° C. (decomp.).

1.2 Preparation of N-(2-amino-4,6-dichloropyrimidine-5-yl)formamide

(i) A solution of 2.35 g (10 mmol) of the product from 1.1 above, in 15g of a 50% aqueous solution of propionic acid, was stirred at 70° C. for7 hours. The mixture was then cooled down and the product filtered off.After washing with water and drying in vacuo, 1.66 g of a white solidwas obtained. This solid was suspended in 50 ml of a 2M solution of K₂CO₃ and the suspension was stirred at room temperature for 2 hours. Thesuspension was filtered and the product was washed with water and driedin vacuo. 1.33 g (64%) of pure product was obtained as an almost whitesolid. ¹ H--NMR (DMSO, 300 MHz)δ: 9.6-10.1 (b, 1H); 8.3 and 8.0 (2s,1H); 7.7 and 7.6 (2s, 2H).

(ii) Proceeding in analogy with (i) above, pivalic acid was employed asthe carboxylic acid in place of propionic acid, and the product wasworked up in a corresponding manner. The yield was 70%.

EXAMPLE 2 Preparation of4,6-dichloro-N'-(dimethylaminomethylene)pyrimidine-2,5-diamine

2.1 Preparation of4,6-dichloro-N,N'-bis(dimethylaminomethylene)pyrimidine-2,5-diamine

A suspension of 4.46 g (25 mmol) of diaminodihydroxypyrimidinehydrochloride in 45 ml of toluene and 15.33 g (100 mmol) of phosphorusoxychloride was heated to 90° C. 7.31 g (100 mmol) of dimethylformamidewas added drop-wise within a span of 45 minutes. The mixture was thenstirred at 90° C. for 20 hours. The reaction mixture was allowed to cooldown, and 100 g of a 10% solution of K₂ CO₃ was slowly added to it. 19.5g of solid K₂ CO₃ was then added so that the pH rose to 7. The productwas extracted with three portions of ethyl acetate. The combined organicphases were dried over MgSO₄ and concentrated on a rotary evaporator.6.44 g of a pale brown solid was obtained, corresponding to a yield of89%. ¹ H--NMR (DMSO, 400 MHz)δ: 2.9-3.1 (4s, 12H); 7.6 (s, 1H); 8.5 (s,1H). ¹³ C--NMR (DMSO, 100 MHz): 33.5; 39.4; 40.4; 134.2; 153.0; 156.7;158.0; 159.1. m.p.: 121.5°-123° C. CHN: calculated for C₁₀ H₁₄ Cl₂ N₆ :C 41.54, H 4.88, N 29.06; found: C 41.4, H 4.58, N 28.6.

2.2 Preparation of N-4,6-dichloro-5-(dimethylaminomethyleneamino)pyrimidine-2-yl!formamide

A suspension of 3 g (10 mmol) of the product from 2.1 above, in 10 ml ofa 50% aqueous solution of acetic acid, was stirred at room temperaturefor 4.5 hours. The product was then filtered off and washed twice with10 ml of water on each occasion. After drying in vacuo, 2.18 g (83%) ofpure product was obtained as a white solid. ¹ H--NMR (DMSO, 400 MHz)δ:2.9-3.1 (2s, 6H); 7.7 (s, 1H); 9.2 (d, 1H); 11.2 (d, 1H). ¹³ C--NMR(DMSO, 100 MHz): 33.6; 39.6; 136.9; 149.6; 153.4; 156.9; 162.5. m.p.:172.5°-174° C. CHN: calculated for C₈ H₉ Cl₂ N₅ : C 36.66, H 3.46, N26.72; found: C 36.7, H 3.07, N 25.9.

2.3 Preparation of4,6-dichloro-N'-(dimethylaminomethylene)pyrimidine-2,5-diamine

A solution of 1.85 g (7.1 mmol) of the product from 2.2 above, in 25 mlof 10% hydrochloric acid, was heated to 40° C. and stirred at thistemperature for 1.5 hours. The reaction mixture was cooled down and thepH was adjusted to 8.7 with 2M K₂ CO₃. The product, which hadprecipitated out, was filtered off and washed with water. After dryingin vacuo, 1.52 g (91%) of pure product was obtained as a white solid.

The spectroscopic data were analogous to those given above.

2.4 Preparation of4,6-dichloro-N'-(dimethylaminomethylene)pyrimidine-2,5-diamine

One-pot process:

A suspension of 4.46 g (25 mmol) of diaminodihydroxypyrimidinehydrochloride in 90 ml of toluene and 15.33 g (100 mmol) of phosphorusoxychloride was heated to 80° C. 7.31 g (100 mmol) of dimethylformamidewas added drop-wise within a span of 60 minutes. The reaction mixturewas then stirred at 80° C. for 16 hours. It was allowed to cool down,and 100 ml of water was then added. The pH was adjusted to 10 using atotal of 8.4 g of Na₂ CO₃. The reaction mixture was heated to 40° C. andstirred at this temperature for 4 hours. It was then cooled down to roomtemperature and neutralized with a 30% solution of NaOH, and the productwas filtered off. After washing with water and drying in vacuo, 5.5 g(95%) of product was obtained as a beige solid. This corresponds to ayield of 89%.

The spectroscopic data were analogous to those given above.

EXAMPLE 3 Preparation of4,6-dichloro-N'-piperidine-1-ylmethylene)pyrimidine-2,5-diamine

3.1 Preparation of4,6-dichloro-N,N'-bis(piperidine-1-ylmethylene)pyrimidine-2,5-diamine

A suspension of 3.57 g (20 mmol) of diaminodihydroxypyrimidinehydrochloride in 70 ml of toluene and 12.27 g (80 mmol of phosphorusoxychloride was heated to 80° C. 9.05 g (80 mmol) of 1-formylpiperidinewas added drop-wise within a span of 60 minutes. The reaction mixturewas then stirred at 80° C. for 22 hours. It was allowed to cool down,and 100 ml of a 1M solution of K₂ CO₃ was then added to it. The pH wasthen adjusted to 7 with NaOH. The product was extracted with threeportions of ethyl acetate. The combined organic phases were dried overMgSO₄ and concentrated on a rotary evaporator. 10.87 g of an oil wasobtained which still contained a large quantity of N-formylpiperidine.The product was purified by suspending in hexane and then filtering. Theyield was greater than 90%. ¹ H--NMR (DMSO, 300 MHz)δ: 8.5 (s, 1H); 7.7(s, 1H); 3.4-3.8 (m, 8H); 1.5-1.9 (m, 12H) .

3.2 Preparation of4,6-dichloro-N'-(piperidine-1-ylmethylene)pyrimidine-2,5-diamine

A solution of 9.9 g (18.2 mmol) of the product from 3.1 above, in 73 gof 10% HCl, was first stirred at room temperature for 4.5 hours and thenstirred at 47° C. for 2 hours. It was cooled down and the pH wasadjusted to 7 using 30% NaOH. The product was filtered off, washed withwater and dried in vacuo. 4.68 g (88%) of product was obtained as a palebrown solid. ¹ H--NMR (DMSO, 300 MHz)δ: 7.55 (s, 1H); 7.4 (s, 2H);3.2-3.7 (m, 4H); 1.5-1.8 (m, 6H).

EXAMPLE 4 Subsequent conversion ofN-(2-amino-4,6-dichloropyrimidine-5-yl) formamide into2-amino-9-butyl-6-chloropurine

4.1 Preparation ofN-(2-amino-4-butylamino-6-chloropyrimidine-5-yl)formamide

A solution of 0.43 g (2 mmol) ofN-(2-amino-4,6-dichloropyrimidine-5-yl)formamide and 0.31 g (4.2 mmol)of n-butylamine in 10 ml of tetrahydrofurane was stirred at roomtemperature for 17 hours. Water was then added to the reaction mixtureand the product was extracted with ethyl acetate. After drying theorganic phase over MgSO₄, and concentrating it on a rotary evaporator,0.49 g of a white solid was obtained which was purified byrecrystallizing in toluene. 0.46 g of pure product was obtained,corresponding to a quantitative yield. ¹ H--NMR (DMSO, 300 MHz)6: 9.0and 8.6 (s and d, 1H); 8.1 and 7.8 (s and d, 1H); 7.0 and 6.75 (2t, 1H);6.5 and 6.4 (2s, 2H); 3.3-3.4 (m, 2H); 1.4-1.6 (m, 2H); 1.2-1.4 (m, 2H);0.9 (t, 3H).

4.2 Preparation of 2-amino-9-butyl-6-chloropurine

A suspension of 0.51 g (2 mmol) of the product from 4.1 above, in 10 mlof diethoxymethyl acetate, was heated to reflux for 3.5 hours. It wasthen completely evaporated, and 30 ml of a 0.5M solution of HCl wasadded to the residue. After 3 hours at room temperature, the yellowsolution was adjusted to a pH of 8 using NAOH, and the resultingsuspension was extracted 3× with ethyl acetate. The combined organicphases were dried and concentrated on a rotary evaporator. 0.46 g (97%)was obtained of the desired product, which was 95% pure (according to ¹H--NMR). ¹ H--NMR (DMSO, 300 MHz)δ: 8.2 (s, 1H); 6.9 (s, 2H); 4.05 (t,2H); 1.6-1.9 (m, 2H); 1.1-1.4 (m, 2H); 0.9 (t, 3H).

4.3 Conversion of 5-(N-ethoxycarbonyl)-2-amino-4,6-dichloropyrimidineinto 2-amino-9-butyl-6-chloro-7,9-dihydropurine-8-one (comparativeexample)

As a comparative example,5-(N-ethoxycarbonyl)-2-amino-4,6-dichloropyrimidine, as a derivative ofan N-5-protected 2,5-diamino-4,6-dichloropyrimidine (EP-A-0552758), wasreacted under conditions which were analogous to those in Example 4.

However, under these conditions,2-amino-9-butyl-6-chloro-7,9-dihydropurine-8-one was obtained ratherthan 2-amino-9-butyl-6-chloropurine.

EXAMPLE 5 Preparation of 2,5-diamino-4,6-dichloropyrimidine

A mixture of 2.35 g (10 mmol) of the product from Example 1.1 in 5 g ofpivalic acid, 10 ml of methanol and 15 ml of water was stirred at 80° C.for 4.5 hours. The precipitated solid was subsequently filtered off andthe filtrate was neutralized with a concentrated solution of NaOH. Itwas then extracted with ethyl acetate and the combined organic phaseswere dried over MgSO₄. Following concentration on a rotary evaporator,1.40 g of a product mixture remained, 65% of which consisted of thedesired product (for a yield of 51%) as determined by ¹ H--NMR. Theproduct was not subjected to further purification.

EXAMPLE 6 Subsequent conversion of 2,5-diamino-4,6-dichloropyrimidineinto 2-amino-9-butyl-6-chloropurine

6.1 2,5-diamino-4-butylamino-6-chloropyrimidine

A suspension of 2.5 g (14 mmol) of 2,5-diamino-4,6-dichloropyrimidine,1.37 g (18.7 mmol) of n-butylamine and 6 ml of triethylamine in 60 ml ofbutanol was stirred at 100° C. for 9 hours. The reaction mixture wasthen cooled down and concentrated to dryness on a rotary evaporator.Water was added to the residue and the product was extracted with ethylacetate. After the organic phase had been dried over Na₂ SO₄ andconcentrated on a rotary evaporator, the residue was suspended in 10 mlof isopropyl ether, and the product was filtered off and dried. 2.24 g(75%) of an orange-red solid was obtained. ¹ H--NMR (CDCl₃, 300 MHz)δ:5.4 (broad s, 1H); 4.6 (s, 2H); 3.4 (t, 2H); 2.7 (s, 2H); 1.6 (m, 2H);1.4 (m, 2H); 0.95 (t, 3H).

6.2 Preparation of 2-amino-9-butyl-6-chloropurine

A solution of 1.0 g (4.63 mmol) of the product from 6.1 above, in 10 mlof dimethylformamide and 10 ml of ethyl orthoformate, was cooled down to0° C., and 0.5 ml of concentrated HCl was added. In conjunction withthis, the temperature rose to 10° C. The mixture was then stirred atroom temperature for 22 hours. It was then completely evaporated, and 40ml of an 0.5M solution of HCl was added to the residue. After 2 hours atroom temperature, the yellow solution was adjusted to a pH of 8 withNaOH, and the resulting suspension was extracted 3× with ethyl acetate.The combined organic phases were dried and concentrated on a rotaryevaporator. 1.1 g (quantitative) was obtained of the desired product,which was 95% pure (by ¹ H--NMR).

The spectroscopic data were analogous to those in Example 4.2.

We claim:
 1. A process for making 2,5-diamino-4,6-dichloropyrimidine ofthe formula ##STR8## the process comprising: (a) in a volume comprisingaminomalonic ester of the formula ##STR9## where R₁ is one of a C₁ -C₆-alkyl group and its salt, cyclizing the aminomalonic ester with one ofguanidine and its salt in the presence of a base, to produce anintermediate comprising one of 2,5-diamino-4,6-dihydroxypyrimidine ofthe formula ##STR10## and its salt; (b) in the intermediate,chlorinating the 2,5-diamino-4,6-dihydroxypyrimidine in the presence ofan amide of the formula ##STR11## where is one of (i) a 5-memberedheterocycloalkyl radical which is optionally substituted on theheteroatom, (ii) a 6-membered heterocycloalkyl radical which isoptionally substituted on the heteroatom, (iii) --NR₃ R₃, where R₃ isone of a C₁ -C₆ -alkyl group and a benzyl group, and (iv) --NR₃ R₄,where R₃ and R₄ each are one of a C₁ -C₆ -alkyl group and a benzylgroup, to produce a 4,6-dichloropyrimidine of the formula ##STR12##where R₅ is --N₂ ; and (c) reacting the 4,6-dichloropyrimidine with acarboxylic acid of the formula

    R.sub.6 --COOH                                             VI

where R₆ is one of (i) a branched C₁ -C₆ -alkyl group, (ii) anunbranched C₁ -C₆ -alkyl group, and (iii) a C₃ -C₆ -cycloalkyl group, inan aqueous alcoholic solution, to produce the substance of the formulaVII.